Chuwa Tei

Mechanism of ischemic mitral regurgitation

The basic mechanism of ischemic mitral regurgitation (MR) is believed augmented leaflet tethering due to the outward displacement of the papillary muscles by left ventricular (LV) remodeling or dilatation. Annular dilatation and LV dysfunction may not be the central mechanism, but contribute to the development of MR in the presence of augmented tethering. Papillary muscle dysfunction was initially expected to cause leaflet prolapse and MR. However, multiple studies have confirmed that papillary muscle dysfunction per se does not usually cause ischemic MR and recent studies further suggest that papillary muscle dysfunction may occasionally attenuate tethering and MR. Although surgical annuloplasty is usually effective to treat ischemic MR, occasional patients with persistent or recurrent ischemic MR after surgical ring annuloplasty even with advanced downsizing suggest the need for approaches to address tethering. Finally, leaflet tethering in patients with ischemic MR can be heterogeneous, indicating the need for individualized approaches to correct ischemic MR in affected patients.

Functional mitral stenosis after surgical annuloplasty for ischemic mitral regurgitation: Importance of subvalvular tethering in the mechanism and dynamic deterioration during exertion

OBJECTIVE Diastolic subvalvular mitral leaflet tethering by left ventricular remodeling that restricts leaflet opening in the presence of annular size reduction by surgery for ischemic mitral regurgitation potentially causes functional mitral stenosis in the absence of organic leaflet lesions. Exercise, known to worsen systolic tethering and ischemic mitral regurgitation, might also dynamically exacerbate such mitral stenosis by increasing tethering. This study evaluates the mechanism and response of such mitral stenosis to exercise. METHODS We measured the diastolic mitral valve area, annular area, and peak and mean transmitral pressure gradient by echocardiography in 20 healthy individuals and 31 patients who underwent surgical annuloplasty for ischemic mitral regurgitation. RESULTS Although the mitral valve area and annular area did not significantly differ in healthy individuals (4.7 +/- 0.6 cm(2) vs 5.2 +/- 0.6 cm(2), not significant), mitral valve area was significantly smaller than the annular area in patients after annuloplasty (1.6 +/- 0.2 cm(2) vs 3.3 +/- 0.5 cm(2), P < .01). The mitral valve area was less than 1.5 cm(2) only after the surgery (P < .01) and was significantly correlated with restricted leaflet opening (r(2) = 0.74, P < .001), left ventricular dilatation (r(2) = 0.17, P < .05), and New York Heart Association functional class (P < .05). Exercise stress echocardiography of 12 patients demonstrated dynamic worsening in functional mitral stenosis (mitral valve area: 2.0 +/- 0.5 cm(2) to 1.4 +/- 0.2 cm(2), P < .01; mean pressure gradient: 1.5 +/- 0.9 mm Hg to 6.0 +/- 2.2 mm Hg, P < .01). CONCLUSIONS Persistent subvalvular leaflet tethering in the presence of annular size reduction by surgery in ischemic mitral regurgitation frequently causes functional mitral stenosis at the leaflet tip level, which is related to heart failure symptoms and can be dynamic with significant exercise-induced worsening.

Waon therapy improves the prognosis of patients with chronic heart failure

BACKGROUND We developed a Waon therapy (soothing warm therapy) and have previously reported that repeated Waon therapy improves hemodynamics, peripheral vascular function, arrhythmias, and clinical symptoms in patients with chronic heart failure (CHF). The aim of this study was to investigate the effect of Waon therapy on the prognosis of CHF patients. PATIENTS AND METHODS We studied 129 patients with CHF in NYHA functional class III or IV who were admitted to our hospital between January 1999 and March 2001. In the Waon therapy group, 64 patients were treated with a far infrared-ray dry sauna at 60 degrees C for 15 min and then kept on bed rest with a blanket for 30 min. The patients were treated daily for 5 days during admission, and then at least twice a week after discharge. In the control group, 65 patients, matched for age, gender, and NYHA functional class, were treated with traditional CHF therapy. The follow-up time was scheduled for 5 years. RESULTS Recent, complete follow-up data on each patient were obtained. The overall survival rate was 84.5% (Kaplan-Meier estimate). Twelve patients died in the control group and 8 patients died in the Waon therapy group at 60 months of follow-up. Cardiac events due to heart failure or cardiac death occurred in 68.7% of the control group but only 31.3% of the Waon therapy group (P<0.01) at 60 months of follow-up. CONCLUSION Waon therapy reduced cardiac events in patients with CHF. This therapy is a promising non-pharmacological treatment for CHF.

Comparison of Blood Glucose Values on Admission for Acute Myocardial Infarction in Patients With Versus Without Diabetes Mellitus

Previous studies have reported that acute hyperglycemia is associated with high mortality after acute myocardial infarction (AMI). However, optimal plasma glucose level may be different between diabetic and nondiabetic patients. The purpose of this study was to assess the relation between admission glucose and in-hospital mortality after AMI in patients with and without diabetes. This study consisted of 3,750 patients who were admitted to the 35 hospitals participating to the Japanese Acute Coronary Syndrome Study (JACSS) group within 48 hours after the onset of AMI. Plasma glucose was measured at the time of hospital admission. In patients without a history of diabetes, there was a linear relation between admission glucose and in-hospital mortality. Nondiabetic patients with a glucose level <6 mmol/L had the lowest mortality (2.5%). As admission glucose increased by 1 mmol/L, mortality increased by 17% (13% to 21%, p <0.001). In patients with a history of diabetes, however, there was a U-shape relation between glucose and mortality. Diabetic patients with glucose 9 to 10 mmol/L had the lowest mortality (1.9%); not only severe hyperglycemia (glucose > or =11 mmol/L, 9.1%, p <0.001) but also euglycemia (glucose <7 mmol/L, 9.4%, p = 0.009) were associated with higher mortality compared to moderate hyperglycemia (glucose 9 to 11 mmol/L, 3.2%). Diabetic patients with admission glucose 9 to 10 mmol/L had the lowest mortality, whereas lower glucose was better in nondiabetic patients. In conclusion, optimal glucose level on admission may be different between diabetic and nondiabetic patients with AMI.

Waon therapy mobilizes CD34+ cells and improves peripheral arterial disease

BACKGROUND We previously reported that Waon therapy upregulates endothelial nitric oxide synthase protein, and augments ischemia-induced angiogenesis in mice with hindlimb ischemia, and it improves limb ischemia in patients with peripheral arterial disease (PAD). The aim of this study was to investigate the underlying mechanism of Waon therapy for the treatment of patients with PAD, and to determine whether Waon therapy can mobilize blood-derived progenitor cells. METHODS 21 consecutive PAD patients received standard medications, and were randomly divided into control (n=10) and Waon therapy groups (n=11). The Waon therapy group received Waon therapy daily for 6 weeks. The control group continued conventional therapy for 6 weeks. Leg pain was scored using a visual analogue scale. The ankle-brachial pressure index (ABPI) and the 6-min walking distance were measured at baseline and 6 weeks after therapy. Frequency of circulating CD34+ progenitor cell numbers was measured by quantitative real-time polymerase chain reaction, and the serum nitrate and nitrite levels were also measured at baseline and 6 weeks after therapy. RESULTS The leg pain score, ABPI and the 6-min walking distance improved significantly after 6 weeks in the Waon therapy group, but not in the control group. Frequency of circulating CD34+ cells increased after 6 weeks of Waon therapy [2.0 ± 1.2 (×10(-4)) at baseline to 3.9 ± 1.9 (×10(-4)), p=0.015], while it remained unchanged in the control group [1.8 ± 1.8 (×10(-4)) at baseline to 1.2 ± 0.9 (×10(-4))]. Serum nitrate and nitrite levels increased significantly after Waon therapy (29.6 ± 17.6 to 36.0 ± 17.7 μmol/ml, p<0.05), but not in the control group (34.4 ± 9.4 to 38.3 ± 8.8 μmol/ml). CONCLUSION Waon therapy mobilized circulating endothelial progenitor cells and improved limb ischemia in patients with PAD. Waon therapy is a highly promising therapy for patients with PAD.

Noninvasive indices of arterial stiffness in hemodialysis patients

The purpose of this study was to evaluate the validity of brachial–ankle pulse wave velocity (baPWV) and the cardio–ankle vascular index (CAVI) as measures of arterial stiffness in hemodialysis (HD) patients. We studied 160 consecutively enrolled HD patients (mean age: 59±13 years; 91 male patients). We measured baPWV and CAVI using a VaSera VS-1000, maximum intima-media thickness (max IMT) of the carotid artery by ultrasonography and blood renal and lipid parameters. As a control, baPWV and CAVI were also measured in age- and gender-matched healthy volunteers. Both baPWV and CAVI were significantly higher in HD patients than in controls (baPWV: 1698±355 vs. 1454±263 cm s−1, P<0.0001; CAVI: 9.3±1.4 vs. 8.9±1.2, P<0.01). BaPWV correlated positively with age (r=0.549, P<0.0001), systolic blood pressure (SBP) (r=0.510, P<0.0001), diastolic blood pressure (r=0.203, P<0.0001), pulse pressure (PP) (r=0.499, P<0.0001), Kt V−1 (r=0.221, P<0.01), Brinkman index (r=0.186, P<0.05) and max IMT (r=0.285, P<0.001). CAVI also correlated positively with age (r=0.562, P<0.0001), SBP (r=0.395, P<0.0001), PP (r=0.490, P<0.0001), Kt V−1 (r=0.216, P<0.01), Brinkman index (r=0.238, P<0.01) and max IMT (r=0.280, P<0.001). Multiple regression analysis demonstrated baPWV and CAVI correlated independently with age and SBP. Receiver operating characteristics (ROC) curve analysis demonstrated that baPWV and CAVI had similar power to predict increases in max IMT. We also measured baPWV and CAVI immediately before and after HD, and showed CAVI was influenced by changes in water volume. Both baPWV and CAVI are therefore useful indices of arterial stiffness in HD patients.

Tacrolimus-eluting stent inhibits neointimal hyperplasia via calcineurin/NFAT signaling in porcine coronary artery model

AIMS The purpose is to elucidate the mechanism by which a newly developed tacrolimus-eluting stent (TES) prevents neointimal hyperplasia after stenting. METHODS AND RESULTS The three major coronary arteries in juvenile swine were randomized to implantation of either a TES or bare metal stent (BMS). Twelve weeks after stenting, the TES showed 29% less neointimal area than the BMS. Immunohistochemical staining showed that the expression of calcineurin was up-regulated in the neointima and media after stenting, and the TES inhibited this up-regulation. Western blotting demonstrated that the expression of calcineurin, nuclear factor of activated T cell (NFAT), and interleukin-2 (IL-2) was lower with the TES than with the BMS. To confirm the effect of tacrolimus on vascular smooth muscle cells (VSMCs) and its mechanism, cultured rat VSMCs were incubated with 12.5 microM of tacrolimus (tacrolimus group) or without tacrolimus (control group). The cell number of the tacrolimus group was significantly lower than that of the control group at 48 h of incubation. Western blotting demonstrated that tacrolimus decreased the expression of calcineurin, NFATc4, and IL-2 of cultured VSMCs. We confirmed that calcineurin small-interfering RNA (siRNA) decreased cell proliferation and the expression of NFATc4 and IL-2 in cultured VSMCs compared with negative control-siRNA. CONCLUSION The newly developed TES inhibited neointimal hyperplasia after stenting via the calcineurin/NFAT/IL-2 signaling pathway, which is one of several mechanisms through which TES inhibits restenosis. Calcineurin may be an important molecular target to prevent restenosis after stenting.

Expression of endothelia and lymphocyte adhesion molecules in bronchus-associated lymphoid tissue (BALT) in adult human lung

BackgroundBronchus-associated lymphoid tissue (BALT) is the secondary lymphoid tissue in bronchial mucosa and is involved in the development of bronchopulmonary immune responses. Although migration of lymphocytes from blood vessels into secondary lymphoid tissues is critical for the development of appropriate adaptive immunity, the endothelia and lymphocyte adhesion molecules that recruit specific subsets of lymphocytes into human BALT are not known. The aim of this study was to determine which adhesion molecules are expressed on lymphocytes and high endothelial venules (HEVs) in human BALT.MethodsWe immunostained frozen sections of BALT from lobectomy specimens from 17 patients with lung carcinoma with a panel of monoclonal antibodies to endothelia and lymphocyte adhesion molecules.ResultsSections of BALT showed B cell follicles surrounded by T cells. Most BALT CD4+ T cells had a CD45RO+ memory phenotype. Almost all BALT B cells expressed α4 integrin and L-selectin. In contrast, 43% of BALT T cells expressed α4 integrin and 20% of BALT T cells expressed L-selectin. Almost all BALT lymphocytes expressed LFA-1. HEVs, which support the migration of lymphocytes from the bloodstream into secondary lymphoid tissues, were prominent in BALT. All HEVs expressed peripheral node addressin, most HEVs expressed vascular cell adhesion molecule-1, and no HEVs expressed mucosal addressin cell adhesion molecule-1.ConclusionHuman BALT expresses endothelia and lymphocyte adhesion molecules that may be important in recruiting naive and memory/effector lymphocytes to BALT during protective and pathologic bronchopulmonary immune responses.

The role of infection in the development of non-valvular atrial fibrillation: Up-regulation of Toll-like receptor 2 expression levels on monocytes

Many studies have suggested that inflammation may participate in the pathogenesis of non-valvular atrial fibrillation (AF). However, it has been unknown by exposure to what the inflammation is caused. Recently, we reported that Toll-like receptor 2 (TLR2) level on monocytes was significantly up-regulated in viral and bacterial infections, but not in non-infectious inflammatory states. Our purpose was to test the hypothesis that expression of TLR2 levels may be up-regulated in patients with non-valvular AF. A total of 48 consecutive patients with non-valvular AF who were hospitalized for catheter ablation were enrolled in this study. TLR2 levels were assayed by using flow-cytometric analysis and compared with volunteers in sinus rhythm (control group, n = 24). Additionally, C-reactive protein (CRP) and interleukin-6 (IL-6) levels were assayed, and the left atrial volume indexes (LAVI) in the non-valvular AF group were measured. The results demonstrated that TLR2 levels in the non-valvular AF group were significantly higher than in the control group (median, 4682 vs. 3866 sites/cell; P < 0.01). Moreover, non-valvular AF patients had significantly higher IL-6 levels than controls. However, there was no significant difference in CRP levels between the two groups. It was observed in 44 AF patients, in whom pulmonary vein isolation was confirmed to be successful, that the LAVI significantly diminished 1 month after ablation (median, 33.6 vs. 29.5 ml/m²; P < 0.001), but not the TLR2 and IL-6 levels. Our results implied that an infectious inflammation may participate in the pathogenesis of non-valvular AF.

Safety, Acceptance, and Physiologic Effects of Sauna Bathing in People With Chronic Heart Failure: A Pilot Report

OBJECTIVES To perform a pilot study and make a preliminary assessment of the safety and acceptance of supervised sauna bathing at moderate temperatures in people with chronic heart failure (CHF). Secondary measures included its impact on exercise tolerance and neuroendocrine concentrations. DESIGN Randomized, controlled, cross-over trial. SETTING Physical medicine and rehabilitation clinic. PARTICIPANTS Six men and 3 women (age, 62-87y) with New York Heart Association Class III and IV CHF. INTERVENTIONS Subjects were randomized into 2 groups and told to maintain their normal medication and activity regimens. One group then began a 3-times-a-week, 4-week sauna bathing program at 60+/-1 degrees C while the other continued with their usual activities and medications. Assignments were then reversed. Sessions were 15 minutes in length but were prolonged an additional 5 minutes for oral temperature increases less than 1.0 degrees C. MAIN OUTCOME MEASURES Patient acceptance, Minnesota Living With Heart Failure Questionnaire (MLWHFQ) scores; treadmill exercise duration and plasma adrenaline, noradrenalin, aldosterone, atrial naturectic factor, adrenomedulin, and endothelin. RESULTS Sauna bathing was well tolerated and no adverse effects were reported. Improvements in MLWHFQ scores and treadmill endurance did not achieve statistical significance on a between-group basis but were more marked after the sauna than during the control phase. Neuroendocrine concentrations showed no clear effect of sauna treatment with a between-group statistically significant difference (P=.049) found only in the case of noradrenalins 24% decrease. CONCLUSIONS Sauna bathing under the moderate and supervised conditions of this study appears to be well tolerated and may be safe for people with CHF. More research is needed to further evaluate the safety and potential benefits of this approach.